Method for the production of 4-(17$g(a)-methyl substituted 3-oxoestra-4 9-dien-11$g(b)-yl)benzaldehyd-(1e or 1z)-oximes

ABSTRACT

The invention relates to a process for the production of 4-(17α-methyl-substituted 3-oxoestra-4,9-dien-11β-yl)benzaldehyde-(1E or 1Z)-oximes of general formula (I), in which R 1  is a hydrogen atom, a C 1-6 -alkyl radical or a C n F 2n+1  radical, whereby n is 1, 2 or 3, R 2  is a C 1-4 -alkyl radical, X is an OH group in E- or Z-position, and Y is an OC 1-6 -alkyl group, an SC 1-6 -alkyl group or an OCH 2 C n F 2+1  group, whereby n is 1, 2 or 3, which provides the target compounds of formula (I) with a high yield and good selectivity.

[0001] The invention relates to a process for the production of4-(17α-methyl-substituted 3-oxoestra-4,9-dien-11β-yl)benzaldehyde-(1E or1Z)-oximes of general formula (I)

[0002] in which R₁ is a hydrogen atom, a C₁₋₆-alkyl radical or aC_(n)F_(2n+1) radical, whereby n is 1, 2 or 3, R₂ is a C₁₋₄-alkylradical, X is an OH group in E- or Z-position, and Y is an OC₁₋₆-alkylgroup, SC₁₋₆-alkyl group or an OCH₂C_(n)F_(2n+1) group, whereby n is 1,2 or 3.

[0003] 4-(17α-Methyl-substituted3-oxoestra-4,9-dien-11β-yl)benzaldehyde-(1E or 1Z)-oximes are alreadyknown. Substances of this type are described in DE 4332283 A1 (EP 0 648778 B1). Because of the advantageous antigestagenic action and slightantiglucocorticoidal action, the compounds are of general interest fortreating a number of hormone-dependent female diseases, such as, forexample, endometriosis.

[0004] The existing process for their production preferably uses as astarting material 5α, 10α-epoxy-estr-9(11)-en-17-one of formula (II)that is protected as a dimethyl ketal on a C-3 as a ketal

[0005] In a first step, in a way that is known in the art, the5α,10α-epoxide of formula (II) is opened by a Cu(f)-salt-catalyzedGrignard reaction with a 4-bromobenzaldehyde ketal, preferably the4-bromobenzaldehyde dimethyl ketal, to 11β-aryl-substituted 5α-hydroxysteroids of formula (III)

[0006] In this case, the yield of the process is not optimal since aportion (3 to 10%) of the 17-oxo group is also attacked, whereby 11β,17α-bisaryl-substituted steroids of formula (IV)

[0007] that are very expensive to separate by chromatography from thedesired 11β-monoaryl-substituted compounds of formula (III) areproduced.

[0008] According to COREY and CHAYKOWSKY (J. Amer. Chem. Soc. 84, 3782[1962]), the mixture of the compounds of formulas (E) and (IV) isconverted mainly into the spiroepoxide of formula (V)

[0009] which is opened by alkali methylate to a 17α-methoxy compound offormula (VI)

[0010] in which R₁ is a hydrogen atom. The compound of formula (IV) isconverted either immediately or after etherification of the 17β-hydroxylgroup with alkyl halides in the presence of bases into compounds ofgeneral formula (VI), in which R₁ is a C₁₋₆-alkyl radical, by acidhydrolysis in the benzaldehydes of formula (VII)

[0011] in which R₁ is a hydrogen atom or a C₁₋₆-alkyl radical. The11β,17β-bisaryl steroids of formula (IV) that are produced in theGrignard reaction as by-products are constantly entrained under theabove-mentioned conditions and ultimately hydrolyzed to the bisaldehydesof formula (VIII)

[0012] These bisaldehydes of formula (VIII) differ in thecrystallization behavior and in their chromatographic properties onlyslightly from the monoaldehydes of formula (VII) and are difficult toseparate quantitatively and thus pose a problem in the production of thecompounds of formula (I) according to the invention.

[0013] The object of this invention is therefore to make available atechnically simpler and more effective process for the production of4-(17α-methyl-substituted 3-oxoestra-4,9-dien-11β-yl)benzaldehyde-(1E or1Z)-oximes of formula (I) that prevents the attack of the Grignardcompound on the C-17 and produces the target compounds of formula (I)with higher yield and better selectivity.

[0014] This object is achieved according to the process of claim 1.

[0015] Since the 17-keto group is converted into the desired17α-methyl-substituted compound before the grignardization, theformation of the by-product of formula (VIII) can be prevented, by whichthe target compounds are obtained with higher yield and purity. Thus,for example, using compound (II) as a starting material according to theprocess of DE 43 32 283 A1, aldehyde (VIIb) can be produced at a yieldof about 5.6% and accordingly oxime (Ic) can be produced at a yield ofabout 3.8%. By the process according to the invention, aldehyde (VIIb)can now be produced at a yield of about 33% or oxime (Ic) can beproduced at a yield of about 23% from olefin (IX), without specialchromatographic conditions having to be used for the purification.

[0016] Preferred embodiments of the invention are indicated in thesubclaims. Because of additional advantages of the invention, referenceis made to the following description and the embodiments.

[0017] According to the invention, the3,3-dimethoxy-estra-5(10),9(11)-en-17-one of formula (IX)

[0018] in which R₂ is a C₁₋₄-alkyl radical, is converted with an activemethylene reagent, which is produced from, e.g., trimethylsulfoniumiodide and a strong base, such as potassium-tert-butanolate, insolvents, such as DMSO, DMF or toluene, into the spiroepoxide of formula(X)

[0019] in which R₂ has the above-indicated meaning, and which, aftercleavage of the 17-spiroepoxy group by alkali or alkaline-earthalcoholate, alkali or alkaline-earth thiolalcoholate or bytrifluoroalkyl alcohols and potassium-tert-butanolate, preferably bysodium methanolate in solvents, such as methanol, DMF or DMSO, is openedto the 17α-CH₂—Y compound of formula (XI)

[0020] in which R₁ represents a hydrogen atom, and R₂ has theabove-indicated meaning, and Y is an OC₁₋₈-alkyl group, SC₁₋₆-alkylgroup or an OCH₂C_(n)F₂₊₁ group, whereby n is 1, 2 or 3.

[0021] By reaction of the 17β-hydroxyl group with alkyl halides orfluoroalkyl halides (halogen=chlorine, bromine or iodine), such asfluoroalkyl iodide, in the presence of strong bases, such as potassiumhydroxide, alcoholates, such as potassium-tert-butanolate, silverfluorides, alkali metals and naphthalene or biphenyl, in inert solvents,such as ethers, tetrahydrofuran (THF) or toluene, the 17β-ethers offormula (XI) are formed, in which R₁ is a C₁₋₆-alkyl radical or aC_(n)F_(2n+1) radical, whereby n represents 1, 2 or 3, and R₂ and Y havethe above-indicated meanings. The compounds of general formula (XI) areepoxidized in a regioselective manner on the 5(10)-double bond. Theepoxidation with hydrogen peroxide and hexachloro- or hexafluoroacetoneis carried out preferably in the presence of catalytic amounts of atertiary amine, such as triethylamine or pyridine, whereby a mixture isproduced from 5α,10α-epoxy- and 5β,10β-epoxy-17α-methyl-substitutedestr-9(11)-ene-3,3-dimethyl ketal of formula (XII)

[0022] in which R₁, R₂ and Y have the above-indicated meanings, whichpreferably is not separated into individual components but rather isopened directly with a 4-bromobenzaldehyde ketal, such as4-bromobenzaldehyde dimethyl ketal, magnesium and Cu(I)CI attemperatures of between −35° C. and room temperature to thecorresponding 3,3-dimethoxy-5α-hydroxy-17α-(methyl-substituted11α,β-benzaldehyde-dimethyl ketal of formula (XIII)

[0023] in which R₁, R₂ and Y have the above-indicated meaning. Thismixture is preferably subjected immediately, without intermediateisolation, to acid hydrolysis to cleave the protective groups, forexample with dilute acetic acid or p-toluenesulfonic acid, in solventssuch as acetone or THF. In this case, a mixture of the11α,β-benzaldehyde derivatives of formula (XIV) is produced

[0024] in which R₁, R₂ and Y have the above-indicated meanings, fromwhich, surprisingly enough, the pure 11β-benzaldehydes are isolated bycrystallization (That is, in the grignardization of the epoxide mixture,two isomeric compounds that differ only slightly in theirchromatographic properties and should actually crystallize in a verysimilar way are produced on the C-11. Surprisingly enough, only the11β-compound crystallizes out, since it is very poorly soluble. Thus,the extensive separation of the 11-α-aldehyde and simultaneously alsothe separation of the non-steroidal by-products are possible by anindividual crystallization. This is especially important since theseby-products would otherwise have an especially disruptive action becauseof the 4× excess of Grignard reagent and would be separable only bychromatography), in which R₁, R₂ and Y have the above-indicatedmeanings, and the aldehyde functions are converted by hydroxylammoniumsalts, preferably hydroxylamine hydrochloride, in the presence of bases,preferably pyridine, at room temperature in a mixture of theE/Z-benzaldoximes of general formula (I), in which R₁, R₂ and Y have theabove-indicated meanings, and X means an OH group in E- or Z-position.The E/Z-benzaldoximes of general formula (I) can be separated byrecrystallization and/or by chromatography, purified and isolated asindividual components.

[0025] In this invention, “alkyl radical” is defined as a branched orstraight-chain alkyl radical. As C₁₋₄- or C₁₋₆-alkyl radicals, forexample, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl ortert-butyl, n-pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,2,2-dimethylbutyl or 2,3-dimethylbutyl group can be mentioned. AC_(n)F_(2n+1) radical is defined as a branched or straight-chainfluoroalkyl radical with 1 to 3 carbon atoms, whereby examples are atrifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl orheptafluoro-isopropyl group. R₁ and R₂ preferably mean a C₁₋₃-alkylradical, especially preferably a methyl group or a trifluoromethylgroup.

[0026] Y preferably means an OC₁₋₃-alkyl radical or an SC₁₋₃-alkylradical, especially preferably a methoxy, ethoxy, isopropyloxy,methylthio or ethylthio group, or a trifluoroethoxy group. The compoundsof formula (I), in which R₁ is a C_(n)F_(2n+1) radical and/or Y is anOCH₂C_(n)F_(2n+1) group, are new.

[0027] Most preferred within the framework of the compounds of formula(I) are the following compounds:

[0028]4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0029]4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime,

[0030]4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0031]4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime,

[0032]4-[17β-Ethoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0033]4-[17β-Hydroxy-17α-(ethoxymethyl)-3-oxoestra4,9-dien-11-yl]benzaldehyde-1E-oxime,

[0034] 4-[17β-Methoxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0035]4-[17β-Hydroxy-17α-(isopropyloxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0036] 4-[17β-Methoxy-17α-(isopropyloxy-methyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,

[0037]4-[17β-Hydroxy-17α-(ethylthiomethyl)-3-oxoestra4,9-dien-11β-yl]benzaldehyde-1E-oximeand

[0038]4-[17β-Hydroxy-17α-(1,1,1-trifluoroethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime.

[0039] The compounds are well bonded to the gestagen receptor, show astrong antigestagenic activity in the animal experiment, have a partialgestagenic activity and exhibit only a slight gluococorticoid receptorbinding [see Table 1 and cf. DE 43 32 283 A1 (EP 0 648 778 B1)].

[0040] Biological Characterization of the Compounds According to theInvention

[0041] The receptor binding affinity was determined by competitivebinding of a specifically binding ³H-labeled tracer and the compound tobe tested to receptors in the cytosol from animal target organs. In thiscase, receptor saturation and reaction equilibrium in the case of thefollowing reaction conditions were sought:

[0042] Progesterone Receptor:

[0043] Uterus cytosol of the estradiol-primed rabbit, stored at −30° C.,in TED buffer (20 mmol of Tris/HCl, pH 7.4; 1 mmol of ethylenediaminetetraacetate, 2 mmol of dithiothreitol) with 250 mmol of saccharose.

[0044] Tracer: ³H ORG 2058

[0045] Reference substance: Progesterone

[0046] Glucocorticoid Receptor:

[0047] Thymus cytosol of the adrenalectomized rat, thymi stored at −30°C.; TED buffer

[0048] Tracer: ³H-Dexamethasone, 20 nmol

[0049] Reference substance: Dexamethasone

[0050] The early-abortive action was determined in the rat aftersubcutaneous administration from the 5th to the 7th day of pregnancy[administration 0.2 ml/animal/day in benzyl benzoate/castor oil (1+4v/v)]. The dose indicates what amount must be given to at least 4animals apiece in comparison to untreated animals, so that a completeinhibition of pregnancy is achieved. TABLE 1 Receptor Binding ofSelected Compounds Proges- Gluco- 100% Early- terone corticoid abortiveAction Receptor Receptor in the Rat [Proges- [Dexa- [mg/ terone =methasone = animal/ Compound 100%] 100%] day] 4-[17β-Hydroxy-(17α- 16576 1.0 (methoxymethyl)-3- oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime 4-[17β-Hydroxy-(17α- 75 67 1.0(methoxymethyl)-3- oxoestra-4,9-dien-11β- yl]benzaldehyde-1Z-oxime4-[17β-Methoxy-(17α- 302 78 1.0 (methoxymethyl)-3-oxoestra-4,9-dien-11β- yl]benzaldehyde-1E-oxime 4-[17β-Methoxy-17α- 12652 1.0 (methoxymethyl)-3- oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime 4-{17β-Hydroxy- 17α- 177 94 3.0 (1,1,1-trifluoroethoxymethyl)-3- oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime Ru 38 486 (Reference) 685 506 3.0

EXAMPLE 1

[0051]4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime(Ia)

[0052] 33 g of4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(VIIa) is dissolved under argon in 250 ml of pyridine and mixed with 5.8g of hydroxylamine hydrochloride. After 2 hours, it is stirred into icewater, the precipitate is suctioned off, washed and dried. The crudeproduct (40 g) is purified by chromatography on silica gel. 20 g of4-[17β-hydroxy-(17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime(Ia) [Melting point: 135 to 145° C. (EtOH/water); α_(D)=+236° (CHCl₃);¹H-NMR: 9.00 (s, 1H, NOH), 8.11 (s, 1H, HC═N), 7.45 (d, 2H, J=8.2,H-3′), 7.17 (d, 2H, J=8.2, H-2′), 5.79 (s, 1H, H-4), 4.38 (d, 1H, J=7.1,H-1 1), 3.58 (d, 2H, J=9.0, CH₂O), 3.43 (s, 3H, OCH₃), 3.25 (d, 2H,J=9.0, CH₂O), 0.48 (s, 3H, H-18)], and 1.5 g of4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime(Ib) [melting point 135 to 146° C. (acetone); α_(D)=+192°; ¹H-NMR: 8.56(s, 1H, NOH), 7.86 (d, 2H, J=8.4, H-3′), 7.33 (s, 1H, HC═N), 7.26 (d,2H, J=8.4, H-2′), 5.79 (s, 1H, H-4), 4.41 (d, 1H, J=7.2, H-11), 3.57 (d,2H, J=9.1, CH₂O), 3.42 (s, 3H, OCH₃), 3.23 (d, 2H, J=9.1, CH₂O), 0.54(s, 31H, H-18) are obtained.

Production of the Starting Compound Stage 13,3-Dimethoxy-estra-5(10),9(11)-diene-17(S)-spiro-1′,2′-oxiranes (Xa)

[0053] 12 g of 3,3-Dimethoxy-estra-5(10), 9(11)-dien-17-one (Ixa) and 9g of trimethylsulfonium iodide in 60 ml of dimethylformamide are mixedwhile being stirred and while being cooled slightly with 5.5 g ofpotassium-tert.-butylate. After 60 minutes, 50 ml of n-hexane and 30 mlof water are added, the phases are separated, and the organic phase iswashed with water. The solution is dried with sodium sulfate andconcentrated by evaporation in a vacuum until crystallization occurs.The recrystallization is carried out from n-hexane.

[0054] Yield: 11 g. Melting point 94 to 97° C.; α_(D)=+164° (CHCl₃);¹H-NMR (δ, ppm, 300 MHz, CDCl₃/TMS): 5.51 (d, J=5.6 Hz, H-11), 3.24 (s,3H, OCH₃), 3.23 (s, 3H, OCH₃), 2.93 (d, 1H, J=5.0 Hz, H-20), 2.66 (d,1H, J=5.0 Hz, H-20), 0.87 (s, 2H, H-18).

Stage 2 3,3-Dimethoxy-17α-(methoxymethyl)-estra-5(10),9(11)-dien-17β-ol(XIa).

[0055] 11 g of the3,3-dimethoxy-estra-5(10),9(11)-diene-17(S)-spiro-1′,2′-oxiranes (Xa) issuspended in 40 ml of methanol and mixed with 40 ml of 3N sodiummethylate solution and refluxed for 2 hours. After water is added, themethanol is distilled off, extracted with tert.-butyl methyl ether andconcentrated by evaporation. The recrystallization is carried out froman ethanol/water mixture. Melting point 73 to 76° C.; α_(D)=+135°(CHCl₃); ¹H-NMR (δ, ppm), 5.56 (m, 1H, H-11), 3.47 (d, 1H, J=9.1 Hz,OCH₂), 3.37 (s, 3H, CH₂OCH₃), 3.24 (s, 3H, 3-OCH₃), 3.23 (s, 3H,3-OCH₃), 3.20 (d, 1H, J=9.1 Hz, OCH₂), 0.88 (s, 3H, H-18).

Stage 33,3-Dimethoxy-5α,10α-epoxy-17α-(methoxymethyl)-estr-9(11)-en-17β-ol and3,3-Dimethoxy-5β,10β-epoxy-17α-(methoxymethyl)-estr-9(11)-en-17β-ol(XIIa):

[0056] 4.2 ml of pyridine, 3.75 ml of hexafluoroacetone-sesquihydrateand 37.5 ml of 50% hydrogen peroxide solution are added in succession toa solution of 30 g (XIa) in 300 ml of methylene chloride. After 4 hoursat room temperature, sodium thiosulfate solution is added, the phasesare separated, the organic phase is washed with sodium bicarbonatesolution and water, dried, and the solvent is evaporated in a vacuum. 31g of crude product (XIIa), which is used directly in the Grignardreaction, is obtained.

Stage 44-[(3,3-Dimethoxy)-5α,17βdihydroxy-17α-(methoxymethyl)-estr-9-en-11α,β-yl]benzaldehyde-dimethylketal (XIIIa):

[0057] 4.5 g of copper(I) chloride is added at −35° C. to a Grignardsolution that is produced from 7.6 g of magnesium, and 72 g of4-bromobenzaldehyde-dimethyl ketal in 100 ml of THF. It is stirred for20 minutes at this temperature, and then a solution of 28 g of epoxidemixture (XIIa) in 70 ml of THF is added in drops. Then, it is allowed toheat to room temperature, mixed with aqueous ammonium chloride solution,and the steroid is extracted with ethyl acetate, the organic phase iswashed neutral, it is dried and concentrated by evaporation in a vacuum.The crude product (Xma) is used directly in the next stage.

Stage 54-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(IVXa):

[0058] 75 g of crude product (XIIIa) is dissolved in 250 ml of 70%acetic acid and stirred under argon for 2 hours at 50° C. It is cooled,methylene chloride is added, the phases are separated, washed neutral,methyl-tert-butyl ether is added, and the organic phase is concentratedby evaporation in a vacuum. 24 g of a pale yellow crude product (XIVa),which contains only a small portion of the 11α-benzaldehyde, isobtained.

Stage 64-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(VIIa):

[0059] 24 g of crude product (XIVa) is dissolved in methylene chloride,mixed with tert.-butyl methyl ether and concentrated by evaporation in avacuum. In this case, the pure 11β-benzaldehyde (VIIa) precipitates incrystalline form, which again is recrystallized in ethyl acetate.

[0060] Melting point 235 to 240° C.; α_(D)=+209° (CHCl₃); ¹H-NMR: 9.97(s, 1H, CHO), 7.80 (d, 2H, J=8.1, H-3′), 7.38 (d, 2H, J=8.1, H-2′), 5.80(s, 1H, H-4), 4.45 (d, 1H, J=7.5, H-11), 3.57 (d, 2H, J=9.2, CH₂O), 3.42(d, 2H, J=10.8, CH₂O), 3.41 (s, 3H, OCH₃), 0.51 (s, 3H, H-18).

Example 2 4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime (Ic)

[0061] 1.75 g of hydroxylamine hydrochloride is added to a solution of10 g of (VIIb) in 100 ml of pyridine at room temperature, and themixture is stirred for 2 hours. It is poured into ice water, theprecipitate is suctioned off, dried on calcium chloride, and the crudeproduct is chromatographed on silica gel. 7 g of4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime(Ic) [melting point 196-198° C. (EtOH/H₂O); α_(D)=+220° (CHCl₃); ¹H-NMR:8.38 (s, 1H, NOH), 8.10 (s, 1H, HC═N), 7.47 (d, 2H, J=8.1, H-3′), 7.20(d, 2H, J=8.1, H-2′), 5.79 (s, 1H, H-4), 4.38 (d, 1H, J=7.3, H-11), 3.58(d, 2H, J=10.8, CH₂O), 3.41 (s, 3H, OCH₃), 3.41 (d, 2H, J=10.8, CH₂O),3.25 (s, 3H, OCH₃), 0.54 (s, 3H, H-18)] and 300 mg of4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime(Id) [melting point 120-138° C. (acetone/n-hexane); α_(D)=+217° (CHCl₃);¹H-NMR: 9.38 (s, 1H, NOH), 7.88 (d, 2H, J=8.9, H-3′), 7.33 (s, 1H,HC═N), 7.26 (d, 2H, J=8.9, H-2′), 5.79 (s, 1H, H-4), 4.39 (d, 1H, J=7.3,H-11), 3.58 (d, 2H, J=10.5, CH₂O), 3.42 (d, 2H, J=10.5, CH₂O), 3.41 (s,3H, OCH₃), 3.26 (s, 3H, OCH₃), 0.54 (s, 3H, H-18) are obtained.

Production of the Starting Compound Stage 1

[0062] 3,3,17β-Trimethoxy-17α-(methoxymethyl)-estra-5(10,9(11)-diene(XIb)

[0063] 12 g of (Xa), 5 ml of methyl iodide and 10 g ofpotassium-tert.-butylate are stirred in 80 ml of tert.-butyl methylether for 4 hours at 30° C. to 40° C. After water is added, the phaseseparation is carried out, the organic phase is washed with water, driedand concentrated by evaporation. The crude product (XIb) isrecrystallized in methanol.

[0064] Melting point 95 to 97° C. (MeOH); α_(D)=+1460 (CHCl₃); ¹H-NMR(δ, ppm): 5.52 (m, 1H, H-11), 3.63 (d, 1H, J=10.7 Hz, OCH₂), 3.38 (s,3H, CH₂OCH₃), 3.31 (d, 1H, J=10.7 Hz, OCH₂), 3.29 (s, 3H, 17β-OCH₃),3.24 (s, 3H, 3-OCH₃), 3.23 (s, 3H, 3-OCH₃), 0.88 (s, 3H, H-18).

Stage 217α-(Methoxymethyl)-3,3,17β-trimethoxy-5≢,10α-epoxy-estr-9(11)-ene and17α-(Methoxymethyl)-3,3,17β-trimethoxy-5β,10β-epoxy-estr-9(11)-ene(XIIb):

[0065] 0.3 ml of pyridine and 0.25 ml of hexafluoroacetone-sesquihydrateare added to 2 g of (XIb) in 20 ml of methylene chloride. At roomtemperature, 2.5 ml of hydrogen peroxide is added in drops, after 4hours sodium sulfite solution is added, the phases are separated, andthe organic phase is washed with sodium bicarbonate and water, dried onsodium sulfate and vacuum-evaporated. The epoxide mixture (XINb) is useddirectly in the next stage.

Stage 311α,β-4-[17α-(Methoxymethyl)-3,3,17β-trimethoxy-5α-hydroxy-estr-9-en-11β-yl]benzaldehyde-dimethylketal (XIIIb)

[0066] 60 mg of copper(I) chloride is added at −35° C. to a Grignardsolution that is produced from 2.4 g of 4-bromobenzaldehyde dimethylketal, and 0.2 g of magnesium in 20 ml of THF. It is stirred for 20minutes at this temperature, and a solution of 1 g (XIIb) in 5 ml of THFis added in drops. Then, the reaction is allowed to reach roomtemperature, the batch is decomposed with aqueous ammonium chloridesolution, the solution is extracted with ethyl acetate, and the organicphase is washed with water; it is dried with sodium sulfate andconcentrated by evaporation. The crude product (XIIIb) (1.5 g) is useddirectly in the next stage.

Stage 44-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehydeVIIb):

[0067] 1.5 g of crude product (XIIIb) is dissolved in 20 ml of acetoneand mixed with 180 mg of p-toluenesulfonic acid. After 1 hour, it isneutralized with aqueous ammonia and diluted with water. In this case,the aldehyde mixture, which is recrystallized from acetone,precipitates. 0.7 g of4-[17β-methoxy-17α-methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(VIIb) is obtained. Melting point 245 to 250° C. (acetone); α_(D)=+193°(CHCl₃); ¹H-NMR: 9.97 (s, 1H, CHO), 7.79 (d, 2H, J=8.1, H-3′), 7.37 (d,2H, J=8.1, H-2′), 5.79 (s, 1H, H-4), 4.44 (d, 1H, J=7.5, H-11), 3.56 (d,2H, J=10.8, CH₂O), 3.42 (d, 2H, J=10.8, CH₂O), 3.41 (s, 3H, OCH₃), 3.25(s, 3H, OCH₃), 0.51 (s, 3H, H-18).

EXAMPLE 34-[17β-Ethoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime(Ie)

[0068] 1.7 g of (VIIc) is stirred in 25 ml of pyridine with 250 mg ofhydroxylamine hydrochloride for 1 hour at room temperature. Then, it ispoured into 100 ml of ice water, the precipitate is suctioned off,washed neutral with water and dried with calcium chloride. The crudeproduct (1.7 g) is purified by chromatography on silica gel. 890 mg of(Ie) is obtained. Melting point 184 to 187° C. (acetone/hexane);α_(D)=+214° (CHCl₃);

[0069]¹H-NMR: 9.10 (s, 1H, CH═N), 7.58 (s, 1H, OH), 7.49 (d, 2H, J=8.4,H-3′), 7.21 (d, 2H, J=8.4, H-2′), 5.78 (s, 1H, H-4), 4.38 (d, 1H, J=6.9,H-11), 3.62 (d, 2H, J=10.8, CH₂O), 3.40 (s, 3H, OCH₃), 3.36 (d, 2H,J=10.8, CH₂O), 1.11 (t, 3H, CH₂CH₃), 0.54 (s, 3H, H-18).

Production of the Starting Compound Stage 13,3,-Dimethoxy-17α-(methoxymethyl)-estra-5(10),9(11)-diene-17β-ethoxyMethyl Ether (XIc)

[0070] 4.2 g of (XIa) is reacted with 15.6 g ofpotassium-tert-butanolate and 76 ml of iodoethane in 400 ml of tolueneat 35° C. within 14 hours. After water is added, the phases areseparated, the organic phase is worked up in a neutral manner, and thesolvent is vacuum-evaporated after drying. The crude product (XIc) isused directly in the next stage without purification.

Stage 23,3,-Dimethoxy-5α,10α-epoxy-17α-(methoxymethyl)-estra-5(10),9(11)-diene-17β-ethoxyMethyl Ether and3,3,-Dimethoxy-5β,10βepoxy-17α-(methoxymethyl)-estra-5(10),9(11)-diene-17β-ethoxyMethyl Ether (XIIc)

[0071] 0.5 ml of pyridine and 0.4 ml of hexafluoroacetone-sesquihydrateare added to 3.3 g of (XIc) in 20 ml of methylene chloride. At roomtemperature, 4.5 ml of hydrogen peroxide is added in drops, and after 4hours, sodium sulfite solution is added, the phases are separated, andthe organic phase is washed with sodium bicarbonate and water, dried onsodium sulfate and vacuum-evaporated. The epoxide mixture (XIIc) is useddirectly in the next stage.

Stage 34-[3,3-Dimethoxy-17β-ethoxy-5α-hydroxy-17α-(methoxymethyl)-estr-9-en-11α,β-yl]benzaldehyde-1,1-dimethylKetal (XIIIc)

[0072] 60 mg of copper(I) chloride is added at −35° C. to a Grignardsolution that is produced from 4.0 g of 4-bromobenzaldehyde dimethylketal, and 0.3 g of magnesium in 20 ml of THF. It is stirred for 20minutes at this temperature, and a solution of 2 g of (XIIc) in 5 ml ofTHF is added in drops. The reaction is then allowed to reach roomtemperature, the batch is decomposed with aqueous ammonium chloridesolution, the solution is extracted with ethyl acetate, and the organicphase is washed with water; it is dried with sodium sulfate andconcentrated by evaporation in a vacuum. The crude product (XIIIc) (4.5g) is used directly in the next stage.

Stage 44-[17β-Ethoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde(VIIc):

[0073] 2.8 g of (XIIIc) is dissolved in 40 ml of acetone. After 1.0 mlof water is added, 1.4 g of p-toluenesulfonic acid is added, and after 1hour, ice water is added. The (VIIc) that precipitates in this case issuctioned off, dried and recrystallized in acetone/hexane and again intert-butyl methyl ether.

[0074] Melting point 164 to 167° C.; α_(D)=+199° (CHCl₃); ¹H-NMR: 9.97(s, 1H, CHO), 7.80 (d, 2H, J=8.1, H-3′), 7.37 (d, 2H, J=8.1, H-2′), 5.79(s, 1H, H4), 4.43 (d, 1H, J=7.5, H-1 1), 3.58 (d, 2H, J=10.8, CH₂O),3.41 (m, 2H, CH₂O), 3.40 (s, 3H, OCH₃), 1.10 (t, 3H, ethyl), 0.51 (s,3H, H-18).

EXAMPLE 44-[17β-Methoxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0075] The production is carried out analogously to Example 2.

[0076] Melting point 90-95° C. (tert.-butyl methyl ether) α_(D)=+1770(CHCl₃); ¹HNMR: 8.10 (s, 1H, HC═N), 7.60 (s, 1H, NOH), 7.48 (d, 2H,J=8.1, H-3′), 7.20 (d, 2H, J=8.1, H-2′), 5.78 (s, 1H, H4), 4.36 (d, 1H,J=7.3, H-11), 3.61 (d, 2H, J=10.8, CH₂O), 3.42 (d, 2H, J=10.8, CH₂O),3.26 (s, 3H, OCH₃), 1.27 (t, 3H, ethyl), 0.53 (s, 3H, H-18)

EXAMPLE 54-[17β-Hydroxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0077] The production is carried out analogously to Example 1.

[0078] Foam (hexane); α_(D)=+226° (CHCl₃); ¹H-NMR: 8.10 (s, 1H, HC═N),7.70 (s, 1H, NOH), 7.48 (d, 2H, J=8.1, H-3′), 7.20 (d, 2H, J=8.1, H-2′),5.78 (s, 1H, H-4), 4.38 (d, 1H, J=7.2, H-11), 3.61 (d, 2H, J=10.8,CH₂O), 3.23 (d, 2H, J=10.8, CH₂O), 3.26 (s, 3H, OCH₃), 1.25 (t, 3H,ethyl), 0.52 (s, 3H, H-18)

EXAMPLE 64-[17β-Methoxy-(17α-(isopropyloxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0079] The production is carried out analogously to Example 1.

[0080] Melting point 192-196° C. decomposition. (Diethyl ether);α_(D)=+215° (CHCl₃);

[0081]¹H-NMR: 8.10 (s, 1H, HC═N), 8.07 (s, 1H, NOH), 7.47 (d, 2H, J=8.1,H-3′), 7.19 (d, 2H, J=8.1, H-2′), 5.79 (s, 1H, H-4), 4.38 (d, 1H, J=6.6,H-11), 3.62 (d, 2H, J=10.8, CH₂O), 3.22 (d, 2H, J=10.8, CH₂O), 3.02 (s,1H, OH), 1.22 (m, 6H, isopropyl), 0.52 (s, 3H, H-18)

EXAMPLE 74-[17β-Hydroxy-(17α-(isopropyloxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0082] The production is carried out analogously to Example 2.

[0083] Melting point 143° C. decomposition. (acetone/n-hexane);α_(D)=+199°(CHCl₃);

[0084]¹H-NMR: 8.10 (s, 1H, HC═N), 8.00 (s, 1H, NOH), 7.48 (d, 2H, J=8.4,H-3′), 7.21 (d, 2H, J=8.4, H-2′), 5.79 (s, 1H, H-4), 4.37 (d, 1H, J=6.9,H-11), 3.61 (d, 2H, J=10.5, CH₂O), 3.43 (d, 2H, J=10.8, CH₂O), 3.26 (s,3H, OCH₃), 1.22 (t, 6H, 6.0 isopropyl), 0.54 (s, 3H, H-18)

EXAMPLE 84-[17β-Hydroxy-(17α-(ethylthiomethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0085] The production is carried out analogously to Example 1.

[0086] Melting point 132 to 137° C. (acetone); α_(D)=+165° (CHCl₃);¹H-NMR: 8.10 (s, 1H, HC═N), 7.93 (s, 1H, NOH), 7.49 (d, 2H, J=8.4,H-3′), 7.20 (d, 2H, J=8.4, H-2′), 5.79 (s, 1H, H4), 4.42 (d, 1H, J=7.2,H-11), 2.96 (d, 2H, J=13.2, CH₂S), 2.90 (s,1H,OH), 2.70 (d, 2H, J=12.9,CH₂S), 1.29 (t, 3H, 10.2, SCH₂CH₃), 0.56 (s, 3H, H18)

EXAMPLE 94-[17β-Hydroxy-(17α-(1,1,1-trifluoroethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime

[0087] The production is carried out analogously to Example 1.

[0088] Melting point 132 to 136° C. (diethyl ether), α_(D)=+182°(CHCl₃); ¹H-NMR: 8.11 (s, 1H, HC═N), 7.60 (s, 1H, NOH), 7.49 (d, 2H,J=8.4, H-3′), 7.20 (d, 2H, J=8.1, H2′), 5.79 (s, 1H, H-4), 4.41 (d, 1H,J=7.2, H-11), 3.93 (m, 2H, CH₂CH₃), 3.82 (d, 2H, J=9.0, CH₂O), 3.50 (m,CH₂CF₃+OH), 0.55 (s, 3H, H-18)

1. Process for the production of 4-(17α-methyl-substituted3-oxoestra-4,9-dien-11-yl)benzaldehyde-(1E or 1Z)-oximes of generalformula (I)

in which R₁ is a hydrogen atom, a C₁₋₆-alkyl radical or a C_(n)F_(2n+1)radical, whereby n is 1, 2 or 3, R₂ is a C₁₋₄-alkyl radical, X means anOH group in E- or Z-position, and Y is an OC₁₋₆-alkyl group, anSC₁₋₆-alkyl group or an OCH₂C_(n)F_(2n+1) group, whereby n is 1, 2 or 3,characterized in that the 3,3-dimethoxy-estra-5(10),9(11)-en-17-one offormula (IX)

in which R₂ has the above-indicated meaning, is converted with an activemethylene reagent in an inert solvent into the spiroepoxide of formula(X)

in which R₂ has the above-indicated meaning, and which, after cleavageof the 17-spiroepoxy group by alkali or alkaline-earth alcoholate,alkali or alkaline-earth thiol alcoholate or by trifluoroalkyl alcoholsand potassium-tert-butanolate in an inert solvent, is opened to the17α-CH₂Y compound of formula (XI)

in which R₁ represents a hydrogen atom and R₂ and Y have theabove-indicated meanings, and this compound optionally is reacted byreaction of the 17β-hydroxyl group with alkyl halides or fluoroalkyliodide in the presence of strong bases in an inert solvent to form the17β-ethers of formula (XI), in which R₁ represents a C₁₋₆-alkyl radicalor a C_(n)F_(2n+1) radical, and R₂ and Y have the above-indicatedmeanings, the compound of formula (XI) is epoxidized on the 5(10)-doublebond, whereby a mixture is produced from 5α,10α]-epoxy- and5β,10β-epoxy-17α-methyl-substituted estr-9(11)-ene-3,3-dimethyl ketal offormula (XII)

in which R₁, R₂ and Y have the above-indicated meanings, which is openedwith a 4-bromobenzaldehyde ketal, magnesium and Cu(I)CI at temperaturesof between −35° C. and room temperature to the corresponding3,3-dimethoxy-5α-hydroxy-17α-methyl-substituted11α,β-benzaldehydedimethyl ketal of formula (XIII)

in which R₁, R₂ and Y have the above-indicated meanings, and which issubjected to acid hydrolysis to cleave the protective groups, whereby amixture of the 11α,β-benzaldehyde derivatives of formula (XIV).

is produced, in which R₁, R₂ and Y have the above-indicated meanings,from which the pure 11β-benzaldehydes of formula (VII) are isolated bycrystallization, in which R₁, R₂ and Y have the above-indicatedmeanings, and the aldehyde function is converted by hydroxylammoniumsalts in the presence of bases, preferably pyridine, at room temperatureinto a mixture of the E/Z-benzaldoximes of general formula (I). 2.Process according to claim 1, wherein the mixture of theE/Z-benzaldoximes of general formula (I) is separated into theindividual components by recrystallization and/or by chromatography. 3.Process according to one of claims 1 or 2, wherein R₁ means a C₁₋₃-alkylradical, preferably a methyl group or a trifluoromethyl group. 4.Process according to one of claims 1 to 3, wherein R₂ means a C₁₋₃-alkylradical, preferably a methyl group or a trifluoromethyl group. 5.Process according to one of claims 1 to 4, wherein Y means anOC₁₋₃-alkyl radical or an SC₁₋₃-alkyl radical, preferably a methoxy,ethoxy, isopropyloxy, methylthio or ethylthio group, or atrifluoromethoxy group.
 6. Process according to one of claims 3 to 5,wherein the following compounds are produced:4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime,4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1Z-oxime,4-[17β-Ethoxy-(17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Hydroxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Methoxy-17α-(ethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Hydroxy-17α-(isopropyloxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Methoxy-17α-(isopropyloxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime,4-[17β-Hydroxy-17α-(ethylthiomethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oximeand4-{17β-Hydroxy-17α-(1,1,1-trifluoroethoxymethyl)-3-oxoestra-4,9-dien-11β-yl]benzaldehyde-1E-oxime.7. Compounds of formula (I), wherein R₁ is a C_(n)F_(2n+1) radical,whereby n is 1, 2 or 3, and R₂, X and Y have the meanings that areindicated in claim
 1. 8. Compounds of formula (I), wherein Y is anOCH₂C_(n)F_(2n+1) group, whereby n is 1, 2 or 3, and R₁, R₂ and X havethe meanings that are indicated in claim 1.